International consensus classification of early tuberculosis states to guide research for improved care and prevention: A Delphi exercise

The current active/latent paradigm of tuberculosis (TB) largely neglects the documented spectrum of disease. Lack of consistency on definitions, terminology and diagnostic criteria for different TB states constrains progress in research and product development required to achieve TB elimination. We reached consensus on a set of conceptual states, related terminology and research gaps through a Delphi process, involving 64 experts, representing a wide range of disciplines, sectors, income settings and geographies. The resulting International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states based on reported symptoms or signs of TB, further differentiated by likely infectiousness. Presence of viable M. tuberculosis and an associated host response are prerequisites for all infection and disease states. Our framework provides a clear direction for TB research, which in time with scientific progress, will improve TB clinical care and elimination policies.


Delphi process -online surveys
The main purpose of two online surveys (see below for details) was to explore areas of agreement and disagreement within the group to inform discussions at the in-person meeting.The first survey explored the groups perspectives on TB states, pathophysiology, natural history and the need for a novel framework and terminology.Results then informed the second survey, which included more focused questions on the key steps in early pathogenesis ofTB, and the conceptual features for a disease state.
Questions for the two surveys were developed and piloted by the SOC with further feedback from the SC.Participants were given 2-3 weeks to complete each survey independently.It was highlighted that the presentation of the results would be anonymous and that responses should not be shared with others to minimise social desirability biases.Most questions required responses on a five-point Likert scale (1.Strongly disagree, 2. Disagree, 3. Neither agree nor disagree, 4. Agree, 5. Strongly Agree) with the opportunity for detailed comments.
Formal criteria for consensus were not used during this stage as the purpose was to explore areas of agreement and disagreement within the group to inform the subsequent in-person meeting.

First Online Delphi survey
The first survey explored perspectives within the group on TB states, pathophysiology, natural history (including the dimensions that define disease and what should be considered disease), and the need for a novel framework and terminology.

Second Online Delphi survey
Results from the first Delphi survey informed the second, which included more focused questions on the key steps in early TB pathogenesis, and the conceptual features for a disease state. .

Delphi process -in-person meeting
The in-person meeting consisted of presentations, workshops, panel and small group discussions and consensus generating activities.Presentations focused on presenting results from the scoping review as well as key areas of agreement and disagreement from the online Delphi surveys.Two sets of four parallel workshops consisted of smaller subgroups of 14-16 participants.The first set of workshops covered key disciplines/areas in TB (bacteriology and transmission; imaging; immunology; public health, modelling and epidemiology; extrapulmonary, and paediatric disease) to discuss key issues that arose from plenary discussions.The second set focused on research gaps, in particular the benefits and challenges for programmatic implementation of the new disease framework (see Appendix 5 for a full meeting agenda).The panel discussions were an opportunity for key stakeholders to reflect and expand on topics discussed in the meeting and to debate issues of controversy.
The in-person meeting consisted of presentations, workshops, panel and small group discussions and consensus generating activities.Key plenary consensus activities included the entire consortium and were moderated by an expert impartial methodologist (TK), with experience in chairing consensus meetings and guideline development but from outside the TB field hence providing impartiality.Ground rules were outlined at the beginning and included respectful interaction, where differences of opinion were taken as helpful opportunities to explore diverse views.Several polls were held throughout the meeting to determine the degree of consensus for each part of the framework.
Attendees were given the opportunity to be voting or non-voting participants in the consensus building process with several (n=7) individuals from e.g.funding organisations contributing as non-voting members.Participants were provided with green and red cards to express either agreement or disagreement.It was emphasised that agreement could encompass views ranging from full agreement to a "can live with" a statement, whereas disagreement represented a fundamental disagreement and a desire wanting to block a statement.Where there was disagreement within the group the aim was to resolve this by discussion but if disagreement remained significant after several rounds of discussion a formal vote was made with an agreed threshold of 70% of voting participants to indicate consensus.
Despite the challenging content and many areas of uncertainty in the underlying evidence, polls indicated that the consensus threshold was exceeded for all key statements reached, therefore no formal votes were required.We captured key considerations and potential reasons for dissent.The full meeting agenda is provided below.Responses to Question: It would be useful to apply multiple (more than two) stages for TB, such as, is carried out for cancer.

Qualitative Responses
Common themes to question: In what ways is a binary paradigm sufficient or insufficient for research?
• Over-simplification • Does not capture complexity of disease • Limits understanding of transmission • Excludes subclinical disease "The binary paradigm is a hopeless simplification of a complex interaction."

Common themes to question:
In what ways is a binary paradigm sufficient or insufficient for programs?
• Early / asymptomatic / subclinical/ intermediate stages may contribute to transmission.
• Simplification is a missed opportunity.
• Diagnostics and treatment are challenging / unclear.

Qualitative Responses
Common themes for research priorities listed by participants.
• Infectiousness of early / subclinical / people without symptoms • Sensitivity / use of CXR and AI software for detection of early stages • Biomarkers for prediction / early detection / identify disease • Better tools for detecting EP and childhood TB • Shorter, simpler, safer regimens for treatment • Strategies for mass-screening, cost-effectiveness and use of X-rays Responses to Question: To what extent do you agree or disagree that this is a key step in TB pathogenesis.
2. As Mtb replicates and spreads locally, the host generates a characteristic immune response that is distinguishable from the response to (many) other pathogens Responses to Question: To what extent do you agree or disagree that this is a key step in TB pathogenesis.

Qualitative Responses
Common themes to question: Are there any other relevant steps to early TB disease pathogenesis that you think should be highlighted?
• Colonization, initial local spread, primary progression • Hematogenous spread/ non-pulmonary • Non-linearity / reversibility "This is all about local spread in the lungs.It is possible that following one of the two early stages, there is dissemination without either spread of bacilli or symptoms that might lead to seeding to other sites.I think this could be a stage?" Section 2: Overall conceptual framework for TB staging Stage 1 -Features consistent with this proposed conceptual stage: • No symptoms related to TB or, if present, not sufficient to seek care • No presence of macroscopically evident pathology related to TB disease (i.e.No disease pathology that would be visible to the naked eye) • Mtb-specific immune response detectable in blood or through skin testing • No viable Mtb in respiratory secretions or aerosols -hence non-infectious via the respiratory route • Potential for progression in the future to a stage that has positive respiratory secretions or aerosols -hence to become infectious via the respiratory route • Can be adequately treated (progression prevented) by therapy for "latent" TB Responses to Question: Do you agree this is conceptually the current definition of "latent" TB Stage 2 -Features consistent with this proposed conceptual stage: • No symptoms related to TB or if present not sufficient to seek care • Presence of macroscopic pathology related to TB (i.e.disease pathology that would be visible to the naked eye) • No viable Mtb in respiratory secretions or aerosols -hence non-infectious via the respiratory route • Potential for progression in the future to a stage that has positive respiratory secretions or aerosols -hence to become infectious via the respiratory route Participants were asked whether they agreed, disagreed (or neither) to the below statements

Statement % Agreeing
1 Our aim should be to have a single TB staging system that is

Diagnostic Criteria
The following diagnostic criteria were listed for TB stages in the survey.Recently "incipient" TB was defined in a WHO/FIND Target Product Profile as "Individuals with tuberculosis infection in whom progression to TB disease has started and who have no symptoms, no radiographic abnormalities suggestive of TB and negative microbiological investigations.Individuals with incipient disease are very likely to develop active TB within a short time of initial evaluation.A subset of patients with incipient disease (primarily immunocompetent patients) will not progress to active disease".The sensitivity of radiographic approach is not defined here, with development in ultra-high resolution CT the spatial resolution of medical imaging can be <0.25mmproviding a very limited window for this state where disease has started to progress but is not visible radiographically.The absence of radiographic abnormalities is at odds with more historic use of the term where the condition was predicated on the presence of radiographic abnormalities.In addition further description of incipient TB in the WHO/FIND TPP, states that incipient TB may include periods of healing and disease regression as evidenced by radiographic and pathological findings which is internally inconsistent.Hence in practice what is considered as incipient TB by this definition will be captured within our Subclinical Non-infectious state.

Responses to
Moreover incipient TB is conceptually defined as having two outcomes (progression or regression) yet TPP diagnostic evaluation was only assessed against one outcome (developing TB within 2 years).Hence the term intends to capture a transition between states predicated on only one future outcome, and not the independent current state.For these reasons the consensus was to not includ it in the framework Reduction in post-TB, improved outcomes through early treatment Delphi 2: Section 1: Key relevant steps in early TB disease pathogenesis 1. Granuloma(s) can fail to control Mtb; this results in further spread of Mtb, and causes a host-derived cellular infiltration within or into the surrounding tissue which can become macroscopically evident and initially occur without development of symptoms.

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Not adequately treated by therapy for "latent" TB • Potential to be distinguished from those without TB disease by an Mtb-specific immune response, TB stage-specific biomarker signature or Mtb antigen/Mtb detection in blood, other bodily fluid or tissue samples.Responses to Question: To what extent do you agree or disagree that this is conceptually an important stage of TB disease to distinguish that if diagnosed could provide benefit to the individual, society or further enable progress towards TB elimination?Stage 3 -Features consistent with this proposed Stage: • No symptoms related to TB or if present not sufficient to seek care • Presence of macroscopic pathology related to TB (i.e.disease pathology that would be visible to the naked eye) • Viable Mtb in respiratory secretions or aerosols -hence infectious via the respiratory route • Not adequately treated by therapy for "latent" TB Responses to Question: To what extent do you agree or disagree that this is conceptually an important stage of TB disease to distinguish that if diagnosed could provide benefit to the individual, society or further enable progress towards TB elimination.Stage 4 -Features consistent with this proposed Stage: • Symptoms related to TB sufficient to seek care • Presence of macroscopic pathology related to TB (i.e.disease pathology that would be visible to the naked eye) • No viable Mtb in respiratory secretions or aerosols -hence non-infectious via the respiratory route Potential for clinical deterioration and progression in the future to a stage that has positive respiratory secretions or aerosols -hence to become infectious via the respiratory route • Not adequately treated by therapy for "latent" TB • Potential to be distinguished from those without TB disease by an Mtb-specific immune response, TB-specific biomarker signature or Mtb antigen/Mtb detection in blood, other bodily fluid or tissue samples.Responses to Question: To what extent do you agree or disagree that this is conceptually an important stage of TB disease to distinguish that if diagnosed could provide benefit to the individual, society or further enable progress towards TB elimination.Stage 5 -Features consistent with this proposed Stage: • Symptoms related to TB sufficient to seek care • Presence of macroscopically evident pathology related to TB disease • Viable Mtb in respiratory secretions or aerosols -hence infectious via the respiratory route Response to Question: Do you agree this is conceptually the current definition of "active" TB Part 3: Criteria for development of diagnostic staging Question: To what extent to you agree or disagree that these criteria are useful and adequately capture conceptual stages Oral swabs -additional cultures, induced sputum, Pathogen or immune signatures for clinically significant disease, Tests that distinguish this from non-TB pathogens as causes, HIV status, Aerosol release 5 Blood based tests for TB disease, POC tests or self-test LAM, RNA signatures, sputum free testing, Prognostic biomarker -including response to treatment.Participants were asked to for their preferred terms for each state -most common terms natural history in this classification meant that people could return to the state of incipient TB after many years of progression, which was felt illogical. .